Catheter for the delivery of therapeutic agents to tissues

ABSTRACT

A catheter for placement of an in situ implant is provided. This catheter may include a first elongate shaft having a proximal end and a distal end, a second elongate shaft having a proximal end and a distal end, a first sharpened distal tip disposed at the distal end of the first shaft and a second sharpened distal tip disposed at the distal end of the second shaft. The first shaft and the second shaft may also be secured to one another at the distal end of the first shaft according to the invention. Still further, according to other teachings, the first sharpened distal tip may extend beyond the second sharpened distal tip in a catheter that practices the invention.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of and claims priority to, U.S.patent application Ser. No. 10,837,612, filed May 4, 2004, now U.S. Pat.No. 6,953,466 and entitled “METHODS FOR DELIVERING A THERAPEUTIC IMPLANTTO TISSUE,” which is a continuation of Ser. No. 09/70931 U.S. Pat. No.6,749,617, filed Nov. 8, 2000, entitled “CATHETER AND IMPLANTS FOR THEDELIVERY OF THERAPEUTIC AGENTS TO TISSUES,” which is acontinuation-in-part of, and claims priority to Ser. No. 09/516,531,U.S. Pat. No. 6,238,406, filed Mar. 1, 2000, entitled “PERCUTANEOUSMYOCARDIAL REVASCULARIZATION GROWTH FACTOR MEDIUMS AND METHODS” which isa divisional of Ser. No. 09/184,220 filed Nov. 2, 1998, now U.S. Pat.No. 6,045,565, which issued Apr. 4, 2000 and is entitled “PERCUTANEOUSMYOCARDIAL REVASCULARIZATION GROWTH FACTOR MEDIUMS AND METHODS” whichclaims the priority benefit of U.S. Provisional Patent Application Ser.No. 60/064,210, filed Nov. 4, 1997, entitled “TRANSMYOCARDIALREVASCULARIZATION GROWTH FACTOR MEDIUMS AND METHOD” and U.S. Pat. No.5,968,059, which issued Oct. 19, 1999, entitled “TRANS MYOCARDIALREVASCULARIZATION CATHETER AND METHOD”.

FIELD OF THE INVENTION

The present invention relates generally to the application ofnon-invasive techniques to the delivery of therapeutic agents.Specifically, the present invention relates to an injection catheter forthe treatment of heart diseases or other organs by the injection oftherapeutic agents and/or placement of implants.

BACKGROUND OF THE INVENTION

A number of techniques are available for treating heart disease anddiseases of other organs percutaneously. An example of one suchtechnique is percutaneous myocardial revascularization (PMR). Thisprocedure is performed to increase blood perfusion through themyocardium of a patient. For example, in some patients, the number oflesions in coronary vessels is so great, or the location so remote inthe patient vasculature, that restoring blood flow to the heart muscleis difficult. Percutaneous myocardial revascularization (PMR) has beendeveloped as an alternative to techniques which are directed atbypassing or removing lesions. PMR is performed by boring holes directlyinto the myocardium of the heart. Positive results have beendemonstrated in some human patients receiving PMR treatments. Theseresults are believed to be caused in part by blood flowing from within aheart chamber through patent holes formed by PMR to the myocardialtissue. Suitable PMR holes have been proposed to be burned by laser, cutby mechanical means, and burned by radio frequency devices. Increasedblood flow to the myocardium is also believed to be caused in part bythe healing response to wound formation, specifically, the formation ofnew blood vessels in response to the newly created wound.

What remains to be provided are improvements and devices for enhancingthe effectiveness of percutaneous myocardial revascularization. Whatalso remains is the extension of these and other refinements to thetreatment of various types of heart disease and diseases of otherorgans.

SUMMARY OF THE INVENTION

The present invention includes devices and methods for treatment ofheart disease and diseases of other organs. The primary focus of thedevices and methods of the present invention is the treatment of heartdisease, but it should be appreciated that, as explained in more detailbelow, the devices and methods can be used to treat the diseases ofother organs. In some instances, the techniques will vary depending uponthe disease being treated.

An exemplary embodiment of the present invention includes, devices andmethods for increasing blood circulation to the myocardium. Circulationcan be increased through patent holes into the myocardium from a heartchamber and from new blood vessel growth. New blood vessels can provideblood supplied from within a heart chamber, such as the left ventricle,and from pre-existing vessels in nearby healthy heart tissue. New vesselgrowth can be promoted by the healing response to wounds created inaccordance with the present invention. New vessel growth can also bepromoted by angiogenic substances supplied to the myocardium inaccordance with the present invention.

One set of methods according to the present invention utilizes implantssuch as tubes implanted into the myocardium, preferably from within theheart, delivered by a catheter. The tubes preferably contain, or arecoated with, an angiogenic substance capable of being released overtime. These tubes can be biodegradable, being absorbed by the body, someembodiment tubes leaving a patent hole in the myocardium surrounded bythe absorbed angiogenic material. Other PMR tubes are not biodegradable,but have lumens therethrough with side holes along the tube length,providing access to the myocardium from with the lumen. Thenon-biodegradable tube can be formed from a metal, polymer or otherbio-stable material. The nonbiodegradable tubes are preferably coatedwith and contain releasable angiogenic material, promoting new vesselgrowth along the length of the tube, where the new vessels may besupplied with blood through the tube side holes. One method utilizes PMRtubes implanted into the myocardium from outside the heart and can beperformed during open heart surgery or during a minimally invasiveprocedure. In one embodiment, a growth factor may be infused in a slowrelease polymer. The growth factor or drug and polymer can be placed ina tube having side poles for drug release. By placing the growth factoror drug in the polymer the growth factor or drug can be slowly releasedinto the myocardium after implantation of the tube therein. In oneembodiment of the tube containing the growth factor or drug and slowrelease polymer, the tube includes side holes and sealed ends.

Another set of methods according to the present invention involvesinjecting angiogenic material into the myocardium. A preferred methodincludes creating small bore holes or direct needle injection, forexample using micro needles, into the myocardium utilizing a catheterwithin the heart. In the case of hole creation, a fluid, gel, polymer(biodegradable or biostable) or adhesive carrying an angiogenic materialis injected into the hole. As the angiogenic substance is absorbed intothe myocardium, in one method, a patent hole remains surrounded bymyocardial tissue treated with angiogenic material. In another method,the injection hole closes, leaving no patent hole. New vessel growth ispromoted by both the healing response to the wound and by the angiogenicsubstance. Blood circulation to myocardial tissue is increased by boththe presence of the patent hole and the presence of new blood vesselssupplied by existing coronary vessels and the heart interior. Analternative method utilizes angiogenic material injected into themyocardium from the exterior of the heart, in conjunction with openheart surgery or during a minimally invasive procedure.

In yet another alternate method, angiogenic materials delivered to theheart to promote new vessel growth. The new vessel growth is theconsequence of the angiogenic material, for example, growth factor andany tissue reaction such as inflammation, rather than wounding thetissue.

Yet another set of methods includes externally wounding the heart andapplying an external patch containing an angiogenic substance to thewound. The wound preferably penetrates into the myocardium. The healingresponse, enhanced by the angiogenic material, promotes new vesselgrowth near the wound. While the wound does not normally penetratethrough to the heart chamber interior, new vessel formation can reachthe chamber interior and also connect with pre-existing vessels inhealthy heart muscle. A wound or series of wounds extending from healthyinto hibernating tissue can create a network of vessels from healthyinto hibernating tissue, supplying the hibernating tissue with blood. Inanother method, an external patch containing angiogenic material isapplied to the heart without significant injury to the heart.

Any therapeutic agent, including small molecular drugs, proteins, genesand cells which could promote angiogenesis, protect tissues (i.e.,cardiac protection), or promote tissue regeneration including VascularEndothelial Growth Factor (VEGF) and Fibroblast Growth Factors (FGFs) isbelieved to be suitable for use with present invention. Carriers for thetherapeutic agents of the present invention include polymers andangiopoietins including biodegradable and biostable hydrogels, anddissoluble polymers. Adhesives suitable for binding the presentinvention include fibrin glues and cyanoacrylates.

The injection of therapeutic agents and implantation of implants such astubes for the placement of patches, is believed to have application tothe treatment of other forms of heart disease in addition to the contextof percutaneous myocardial revascularization. Some of these diseasesinclude, for example, heart failure, myocardial infarction, and cancers,for example of the bladder, liver and kidneys.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective, cutaway view of a human heart having a PMRcatheter inserted within, having punctured holes into the myocardiumfrom within and filled the holes with angiogenic material;

FIG. 2 is a partial cross-sectional schematic side view of a PNMcatheter disposed within a guide tube;

FIG. 3 is a partial cross-sectional view of the PMR catheter of FIG. 2in accordance with the present invention;

FIG. 4 is a side cross-sectional view of a PMR spike according to thepresent invention, having a lumen and side holes;

FIG. 5 is a cross-sectional view of a catheter assembly in accordancewith the present invention, for placement of an in situ implant;

FIG. 6 is a perspective, cut-away view of a human heart having anexternal wound to the wall of the left ventricle;

FIG. 7 is a perspective, cut-away view of the wounded heart of FIG. 6having angiogenic substance and patch applied;

FIG. 8 is a cross sectional view of a catheter assembly in accordancewith the present invention;

FIG. 9 is a cross sectional view of a detailed catheter assembly of FIG.8;

FIG. 10 is a cross sectional view of a catheter portion of the catheterassembly of FIG. 7;

FIG. 11 is a cross sectional view of a catheter tip showing a radiopaquemarker disposed within the catheter;

FIG. 12 is a view of the catheter tip of FIG. 11 showing the radiopaquemarker distal of the catheter tip;

FIG. 13 is a view of the catheter tip of FIG. 11 showing the radiopaquemarker disposed within the myocardium;

FIG. 14 is a longitudinal cross sectional view of an alternateembodiment of the catheter in accordance with the present invention;

FIG. 15 is a proximal end view of an embodiment of a manifold inaccordance with the present invention;

FIG. 16 is a distal end view of an embodiment of a Luer fitting inaccordance with the present invention; and

FIG. 17 is a cross sectional view of an alternate manifold in accordancewith the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now to the drawings wherein like reference numerals indicatelike elements throughout the several views, a human heart 20 having anaorta 22, a left ventricle 30, and a myocardium 28 is illustrated inFIG. 1. As shown for one embodiment of the invention, percutaneouscatheter 24 is disposed within a guide catheter 26, which is disposedwithin aorta 22 and left ventricle 30. Catheter 24 has finished creatinga series of holes or punctures 32 and filling them with avascularization promoting, or angiogenic, substance 34 for the treatmentof ischemic tissue. Angiogenic substance 34 is preferably carried in abiodegradable substance, such as, for example, gelatin, hyaluronic acid,albumin, and polyesters that are released over time. The carriermaterial can be adhered to secure the angiogenic substance in place andresist forces attempting to expel the materials into the heart chambers.The carrier need not, however, be biodegradable. The carrier materialcan include radiopaque material. The radiopaque material allowsvisualization of hole depth and expelled or washed out material.

After degradation of the biodegradable material, holes 32 can remainpatent while the angiogenic material has promoted blood vessel growthnear the hole walls and into the myocardium. Holes 32 can also close,leaving no patent hole but leaving newly formed blood vessels. Theinventors believe the new vessel growth will be significantly enhancedby the angiogenic substance, thereby increasing blood flow from insidethe left ventricle to the myocardium of the left ventricle. New vesselgrowth is expected to join with other vessels at anastomoses, forming alarger network of blood vessels in the myocardium supplied by blood fromthe left ventricle and blood from other vessels supplied by coronaryarteries. Preferred substances for encouraging tissue growth of ischemictissue include Vascular Endothelial Growth Factor (VEGF), FibroblastGrowth Factor (FGF), PDGF, angiopoietins (Ang1, Ang2), estrogen or geneseffecting the production of growth factors such as MCP-1 and HIFI-α,DEL-1, Tat, and Akt.

Catheter 24 can be used to treat heart failure and the heart aftermyocardial infarction by directly injecting agents or implants into thediseased myocardium. Agents for treating heart failure include positiveinotropic agents, diuretics, vasodilators, neurohormonal antagonists,calcium channel blockers, anti-ischemic agents, antiarrhythmics,anticoagulants; and natruiretic peptides, such as BNP, endothelian,growth hormone, and adenosine receptor antagonists. Survival genes orproteins may be used to treat heart tissue following myocardialinfarction. These include, for example, AKT kinases, cyclases, i.e.,adenylyl cyclase VI, IkB, or any anti-apoptotic molecule or protein, orother molecules which aid in heart muscle regeneration, such as theangiogenesis inducing agents listed above.

Catheter 24 can be used to treat cancers by injecting agents or implantsinto solid tumors or cancerous tissues, which are accessibleendoluminally. Such agents for treatment of cancers include, forexample, cytoxic proteins, such as FASL and TK/gancyclovir; orcytostatic agents, such as Rb or p53, or the genes encoding theseproteins. Anti-angiogenic molecules can also be injected to treatcancer; these include, for example, endostatin, angiostatin,thrombospondin, dox-RGD, antibodies to or small molecule inhibitors ofVEGF and other endogenous angiogenic molecules or other small moleculessuch as paclitaxel, 5-FU, etc.

Similarly to the substance for encouraging tissue growth used for thePMR treatment, the agents used to treat heart failure and the heartafter myocardial infarction, as well as the agents used to treat cancer,can be incorporated into a carrier material. This material is preferablybiodegradable or dissoluble but can be substantially bio-stable ornon-biodegradable. The carrier material preferably holds the therapeuticagents in proximity to the tissue to be treated.

Such carriers can include, among others, biodegradable polymers suitablefor use in the present invention include: poly(L-lactide) (PLLA),poly(D,L-lactide) (PLA), poly(glycolide) (PGA), poly(L-lactide-co-D.L.Lactide) (PLLA/PLA), poly(L-lactide-coglycolide) (PLA/PGA),poly(glycolide-co-trimethylene carbonate) (PGA/PTMC), polydioxanone(PDS), polycaprolactone(PCL), polyhydroxybutyrate (PHBT),poly(phosphazenes), poly(D,L-lactide-co-caprolactone) (PLA/PCL),poly(glycolide-cocaprolactone) (PGA/PCL), poly(phosphase ester) andpolyanhydrides. Other materials suitable for mixing with growth factorsinclude, for example: hydrogels, polyethylene oxide and its copolymers,polyvinylpyrolidone, polyacrylates, polyesters, gelatins, collagens,proteins, alginates, karaya gum, guar gum, agar, algin, carrageenans,pectins, xanthan, starch based gums, hydroxyalkyl and ethyl ethers ofcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, andpolyurethanes.

FIG. 2 is a partial cross sectional schematic side view of oneembodiment of catheter 24 including an outer shaft 36 and inner shaft38. Inner shaft 38 preferably includes a distally disposed cutting tip40 having an opening 42 in fluid communication with a lumen 52 throughtip 40. Inner shaft 38 preferably includes a proximal shaft portion 44and a more flexible distal shaft portion 46. Inner shaft 38 is connectedto a motor 48 for rotation of inner shaft 38 about the longitudinal axisthereof relative to outer shaft 36 which is fixed against rotation.Motor 48 is connected to a power supply shown schematically as a battery50. The spacing between outer shaft 36 and inner shaft 38 should beenough to allow sufficient rotation of inner shaft 38 relative to outershaft 36. Rotation is desirable as rotation acts to obliteratemyocardial material within cutting tip 40, leaving a large diameter,patent hole. In one method, inner shaft 38 is not rotated relative toouter shaft 36, allowing injection of angiogenic material withoutleaving a large diameter myocardial hole. Inner shaft 38 is slidablelongitudinally relative to outer shaft 36.

FIG. 3 is a side and partial cross sectional view of inner shaft 38 ofPMR catheter 24 shown schematically in FIG. 2. Cutting tip 40 which ispreferably a hypodermic needle tip having a distally disposed cuttingedge 42 at an acute angle to the longitudinal axis of inner shaft 38.Tip 40 defines a lumen 52 in fluid communication with opening 42. Lumen52 and opening 42 can be used to carry angiogenic materials andadhesives through tip 40, injecting it in a hole recently bored by tip40. In some embodiments, radiopaque material is included with theangiogenic material. Radiopaque material or any contrast material usedwith guidance technology such as fluoroscopy, MRI or echocardiographyallows confirmation of successful injection, visualization of holedepth, and visualization of any material expelled or washed from thehole. Although tip 40 is preferably formed from a hypodermic needle tip,it may be formed from other suitably durable and biocompatible materialsas known to those skilled in the art. Tip 40 can have an outsidediameter of, for example, 0.036 inches.

Proximal shaft 44 is preferably formed from a stainless steel hypotubewhich is more rigid than distal. shaft 46. Shaft 44 defines a lumen 56extending longitudinally therethrough. Proximal shaft 44 preferablyextends the substantial majority of the length of inner shaft 38, toenhance the pushability and torqueability of inner shaft 38. It shouldbe understood that although hypotube construction is preferred forproximal shaft 44, shaft 44 could be formed in the same manner as distalshaft 46 as described in more detail below or from another sufficientlytorqueable and pushable construction as known in the art.

Distal shaft portion 46 is preferably more flexible than proximal shaft44 to enhance trackability of inner shaft 38 proximate cutting tip 40.Distal shaft 46 can be formed from a helical coil 58 defining anelongate lumen 60 therethrough in fluid communication with lumen 56 ofproximal shaft 44 and lumen 52 of cutting tip 40. Coil 58 can besurrounded by a polymer sheath 62. Sheath 62 may be PTFE, a shrink wrapor other similar biocompatible material known to those skilled in theart. The inside coil 58 forming the lumen wall of lumen 60 can besimilarly coated. Shaft 46 can also be formed from an elastic alloy suchas Nitinol.

Tip 40 and proximal shaft 44 can be connected to distal shaft 46 by twoshort tubular segments 64 and inserted within lumens 56 and 60, and 56and 52, respectively. Tubular segments 64 can be small diameter hypotubesegments or other sufficiently durable and biocompatible tubular membersdefining lumens in fluid communication with lumens 52, 56 and 60. Anadhesive, braze or swage can be used to attach segments 64 to shafts 44and 46 and tip 40.

In use, cutting tip 40 of inner shaft 38 can be deliveredintravascularly to the heart wall and myocardium. by a catheter tube ortubes. In one embodiment, once cutting tip 40 has been. brought intocontact with the heart wall, motor 48 can be activated to rotate cuttingtip 40 and consequently blade 42. By further advancing cutting tip 40into the myocardium of the heart, tissue in the path of the rotatingblade will disintegrate. The disintegrated tissue can be aspiratedthrough the lumen 52 extending through inner shaft 38. It can beappreciated that cutting tip 40 can penetrate the myocardium withoutbeing rotated. However, disintegration of tissue will generally notoccur without rotating of tip 40.

Generally, the hole depth is preferably between ⅓ and ¾ the thickness ofthe heart wall. The hole, however, could completely penetrate themyocardium for delivery of therapeutic agents to the pericardial space.The specific hole depth is determined on a case by case basis for eachpatient. Ultrasonic techniques may be used to view the patient's heartto determine the appropriate depth of the holes. In one method,radiopaque or contrast material is injected into the hole, in part todetermine hole depth. A hole can be cut or formed, followed byradiopaque material injection and hole depth visualization using amethod such as fluoroscopy. The cutting, radiopaque injection, and depthvisualization cycle can be repeated until the desired hole depth isachieved. The depth of the holes will be generally proportional to thedepth of penetration of cutting tip 40 into the myocardium. The rotationrate of cutting tip 40 may vary upon the character of the heart tissueencountered but should be rapid enough to disintegrate the tissue in thepath of the cutting tip. The imaging agent can be incorporated into ormixed with a growth factor drug.

Inner shaft 38 and lumen 52 can be used to deliver angiogenic substancesand adhesives and other carriers within the myocardium while tip 40 isstill in place. In a preferred method, adhesives cure after leaving thetip. One method uses moisture cured adhesives. Once the angiogenicmaterial has adhered to the walls of the hole bored into themyocardium., the angiogenic substance is more likely to remain in placewithin the myocardium. Adhesives preferably bind angiogenic material tothe hole walls with a strength sufficient to resist immediate expulsionfrom the hole while being degradable or absorbable so as to allowdiffusion of angiogenic material from the adhesive and absorption ofangiogenic material into the myocardium. Inclusion of a fluoroscopicagent or radiopaque material with the angiogenic material can aid invisualizing expelled material.

Referring now to FIG. 4, an implant, for example, tube 66 is illustratedimplanted within a myocardial region 78. Tube 66 can be eitherbiodegradable or permanent such as a non-biodegradable metal or polymer.PMR tubes are believed to operate by several mechanisms. First, drivingthe tubes into the myocardium is believed to trigger a healing response,including neovascularization. Second, the tubes can deliver angiogenicagents to the myocardium over a period of time. This can operate topromote new vessel growth in conjunction with, and apart from, thehealing response. The delivery of growth factors can also speed thehealing response generally, minimizing any adverse reaction to theimplanted tube. Third, tubes having lumens and side holes can provide ahole within the tube for blood flow into the myocardium through the tubeor a space for the therapeutic agent and slow release polymer.

A preferred embodiment tube has a circular cross section, a lumen 70,side holes 74, proximal port 80 and distal port 68, allowing blood flowthrough proximal port 80, lumen 70, side holes 74, distal port 68 andinto myocardial tissue. Tube 66 is preferably formed of a biodegradablepolymeric material, discussed further below. One embodiment has tubularwalls porous to blood passage rather than larger, discrete holes.Another embodiment has no lumen and is formed of time-releasedtherapeutics embedded in biodegradable material, such that theangiogenic substance is delivered within the myocardial tissue and thetube dissolves, possibly leaving a patent hole surrounded by tissuetreated with angiogenic substance. While the preferred tube embodimenthas a round cross-section, other embodiments have triangular, square,and elongate rectangular cross sections. Tube 66 preferably has acutting tip 72 for easing insertion into the myocardium. Tubes can alsohave barbed outer surfaces to aid in retaining the spike within themyocardium. The tube can include radiopaque material or contrast as anaid in visualizing fluoroscopically where tubes have already beenimplanted. The tubes can be implanted in a pattern, leading from healthytissue to hibernating tissue, creating a network of new blood vesselscarrying both blood supplied from coronary arteries and the heartchamber itself.

The tube can be delivered through the lumen of a catheter from within aheart chamber. Tubes can also be delivered externally into themyocardium, either during open heart surgery or during a minimallyinvasive procedure. Tubes delivered externally preferably have lumens,side holes, closed proximal ends to minimize blood loss, and outsidesurface barbs to lessen the risk of the tube being expelled from theheart muscle. In a minimally invasive procedure, the PMR tubes can beinjected through an elongate catheter into the pericardium. The PMRtubes can be injected entirely through the myocardium or can stop shortof such penetration. The inventors believe the externally inserted PMRtubes can significantly promote vascularization within the myocardium,even where the PMR tubes do not penetrate through to the endocardium.

Although tubes 66 have been described herein with respect to PMR, it isanticipated that the tubes can be used for the treatment of heartfailure and the heart after myocardial infarction by incorporating thetherapeutic agents described above with respect to these conditions. Itis also believed that the tubes could be used for treating cancer byincorporating the therapeutic agents described above.

FIG. 5 is a cross-sectional view of a catheter 91 for placement of an insitu implant including a therapeutic agent. Catheter 91 includes anelongate outer tube 92 and an elongate inner tube 93 having a lumen 94extending therethrough. An annular lumen 95 defined between tubes 92 and93. At the proximal end of tubes 92 and 93 (not shown) is a suitablemanifold, as known to those skilled in the art, including a firstinfusion port in fluid communication with lumen 94 and a second infusionport in fluid communication with lumen 95. The ports should beseparately connected to the respective lumens 94 and 95 such that fluidsinfused through each port are not co-mingled in the lumens. In additionto the proximal manifold holding the relative positions of tubes 92 and93, a web or adhesive weld 96 disposed at the distal. end of tubes 92and 93 can substantially fix the tubes relative position. Extendingdistally from tube 92 is a sharpened tube, which could be a hypotube 97.Extending from tube 93 and through the lumen of tube 97 is a sharpenedtube 98 having a lumen extending therethrough. The lumen of tube 98 isin fluid communication with lumen 94 and the lumen through tube 97 is influid communication with lumen 95.

Tubes 92 and 93 should be long enough and flexible enough to be advancedintraluminally to a desired body organ such as the heart, liver,bladder, or kidneys. The diameter of tube 92 should be sufficientlysmall to be advanced through the desired body lumen. Tubes 92 and 93 canbe formed from biocompatible polymers or other materials known to thoseskilled in the art. Tubes 97 and 98 can be adhered to tubes 92 and 93respectively by materials known to those skilled in the art. Tubes 97and 98 can be hypotubes made from a metallic material or from asufficiently rigid polymer or other material that they can be advancedinto tissue for fluid injection therein.

As an alternative to the tubular implants described above, catheter 91can be used to form an in situ implant. For example, a polymer could bepre-mixed with any of the therapeutic agents described above fortreatment of the heart, liver, kidneys, bladder or other organs andsolid tumors. The polymer pre-mix could be infused through, for example,lumen 94 into a tissue to be treated. At the same location across-linking agent could be infused through lumen 95 into the tissue.This would result in the polymer becoming cross-linked and solidifyingin tissue. The cross-linking agent can also be mixed into a contrastsolution such that the implants would become radiopaque. An examplepolymer to be pre-mixed with the therapeutic agent is alginate polymer,which can be cross-linked by multivalent ions. In another example, thepolymer, if a polycation, gelatin, chitosan or the like which can bedelivered through one lumen and the therapeutic agent if a polyanionsuch as DNA can be delivered through the second lumen. A polyelectrolytecomplex will be formed when the polycation mixes with the polyanion,forming a solid material.

The polymer can be bio-stable or biodegradable, including dissolublepolymers. After the implants are placed in the tissue, the therapeuticagent is slowly released. The rate of release of the therapeutic agentto the surrounding tissue may be controlled by, for example, 1)diffusion of the agent through the polymer implant if the polymerimplant is bio-stable; 2) by the rate of polymer degradation ordissolution if the implant is made of a biodegradable or dissolvableimplant; or 3) by the rate of ion exchange if the implant is formedusing two oppositely changed polyelectrolytes. In this manner,therapeutic agents may be delivered to tissue over periods of days,weeks, or a longer period of time.

An alternate embodiment of an implant which can be injected through asingle lumen catheter such as that shown in FIG. 3 includes geneticallyengineered cells (such that they over express specific therapeuticproteins) grown in scaffolding polymers, that can be implanted intotissue. The implants may contain specific cells which have therapeuticproperties in certain instances such as endothelial cells. In analternate embodiment, the implants may also be healthy tissue taken fromone site and transplanted to a diseased site using, for example, aneedle injection catheter such as that shown in FIG. 3.

Referring now to FIG. 6, another procedure for promoting vascularizationwithin the myocardium is illustrated. Heart 20 has a wound 84 externalto the left ventricle. Wound 84 is formed of a series of incisions 86through the pericardium into the myocardium. In one method, the woundsare formed as a series of needle punctures rather than wedge likeincisions as illustrated in FIG. 6. Referring now to FIG. 7, after woundformation, angiogenic substances, wound healing agents, and growthfactors can be applied to the wound, promoting a healing response.Growth factors and healing agents may be included to promote healing ofthe wounds to the heart, desirable even apart from the angiogenic goal.A patch 90 can then be applied over the wound, holding the angiogenicsubstance in place over the wound. In one embodiment, the patch is heldin place with adhesives.

Patch 90 is preferably biodegradable, capable of being absorbed by thebody after it is no longer needed. One patch includes a reservoir ofangiogenic substance that leaches out the inside of the patch, supplyingmore wound healing and angiogenic compound over time.

Externally wounding the heart and applying a patch can be performed inconjunction with open heart surgery, where the heart is available forsuch a procedure. Minimally invasive procedures can also be used toaccess the heart for externally wounding the heart, creating wound andapplying patch through a relatively small opening. Applicants believeexternally wounding the heart triggers a healing response within themyocardium, including the formation of new blood vessels to the woundedarea. While the incisions preferably do not penetrate through the entirethickness of the chamber wall, applicants believe the incisions withinthe myocardium trigger new blood vessel growth within the myocardiumwhich can be supplied by vessels within the heart chamber or by othercoronary vessels. While it is believed to be preferable to wound thetissue prior to placement of the patch, the patch is believed to havetherapeutic value as well when placed on tissue that has not beenwounded.

A variety of angiogenic substances and growth factors can be used inaccordance with the present invention. Growth factors such as FibroblastGrowth Factor (FGF, FGF-1, FGF-2), Vascular Endothelial Growth Factors(VEGF) (all constructs including VEGF-2) and Endothelial MitogenicGrowth Factors are among the growth factors preferred for use with thepresent invention. Angiogenic substances such as estrogen, includingestradiol (E2), estriol (E3) and 17-Beta Estradiol are also believedsuitable for use with the present invention. Estrogen is believed toinduce angiogenesis and increase permeability. This provides increasedlocal blood circulation through neovascularization. Gene transfer intothe heart tissue can be done as well.

The therapeutic agents used in the present invention also include, forexample, pharmaceutically active compounds, proteins, oligonucleotides,ribozymes, anti-sense genes, DNA compacting agents, gene/vector systems(i.e., anything that allows for the uptake and expression of nucleicacids), nucleic acids (including, for example, recombinant nucleicacids; naked DNA, cDNA, RNA; DNA, cDNA or RNA in a noninfectious vectoror in a viral vector which may have attached peptide targetingsequences; antisense nucleic acid (RNA or DNA); and DNA chimeras whichinclude gene sequences and encoding for ferry proteins such as membranetranslocating sequences (“MTS”) and herpes simplex virus-1 (“VP22”), andviral liposomes and cationic polymers that are selected from a number oftypes depending on the desired application. For example, biologicallyactive solutes include anti-thrombogenic agents such as heparin, heparinderivatives, urokinase, PPACK (dextrophenylalanine proline argininechloromethylketone), rapamycin, probucol, and verapamil; angiogenic andanti-angiogenic agents; anti-proliferative agents such as enoxaprin,angiopeptin, or monoclonal antibodies capable of blocking smooth musclecell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatoryagents such as dexamethasone, prednisolone, corticosterone, budesonide,estrogen, sulfasalazine, and mesalamine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin and thymidine kinase inhibitors; anestheticagents such as lidocaine, bupivacaine, and ropivacaine; anticoagulantssuch as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containingcompounds, heparin, antithrombin compounds, platelet receptorantagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, aspirin, prostaglandin inhibitors, platelet inhibitors andtick antiplatelet factors; vascular cell growth promoters such as growthfactors, growth factor receptor antagonists, transcriptional activators,and translational promoters; vascular cell growth inhibitors such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vascoactive mechanisms, and combinationsthereof. Cells of human origin can be used (autologous or allogeneic) orfrom an animal source (xenogeneic), genetically engineered if desired todeliver proteins of interest at the transplant site. The delivery mediacan be formulated as needed to maintain cell function and viability.

Polynucleotide sequences useful in the practice of the present inventioninclude DNA or RNA sequences having a therapeutic effect after beingtaken up by a cell. Examples of therapeutic polynucleotides includeanti-sense DNA and RNA; DNA coding for an antisense RNA; or DNA codingfor tRNA or rRNA to replace defective or deficient endogenous molecules.The polynucleotides of the invention can also code for therapeuticpeptides. A polypeptide is understood to be any translation product of apolynucleotide regardless of size, and whether glycosylated or not.Therapeutic polypeptides include as a primary example, thosepolypeptides that can compensate for defective or deficient species inan animal, or those that act through toxic effects to limit or removeharmful cells from the body. In addition, the polypeptides or proteinsthat can used include without limitation, angiogenic factors includingacidic and basic fibroblast growth factors, vascular endothelial growthfactor, epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor andinsulin-like growth factor; growth factors; cell cycle inhibitorsincluding CDK inhibitors; thymidine kinase (“TK”) and other agentsuseful for interfering with cell proliferation, including agents fortreating malignancies; and combinations thereof. Still other usefulfactors, which can be provided as polypeptides or as DNA encoding thesepolypeptides, include monocyte chemoattractant protein (“MCP-1”), andthe family of bone morphogenic proteins (“BWPs”). The known proteinsinclude BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr1), BMP-7 (OP-1), BMP-8,BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.Currently preferred BMPs are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6and BMP-7. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively or, in addition, molecules capable of inducingan upstream or downstream effect of a DMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNAs encodingthem.

In one exemplary embodiment of the present invention, the medical devicehas recombinant nucleic acid incorporated therein, wherein therecombinant nucleic acid comprises a viral vector having linked theretoan exogenous nucleic acid sequence. “Exogenous nucleic acid sequence” isused herein to mean a sequence of nucleic acids that is exogenous to thevirus from which the vector is derived. The concentration of the viralvector, preferably an adenoviral vector, is at least about 10¹⁰ plaqueforming units (“p.f.u.”), preferably at least about 10¹¹, p.f.u.Alternatively, the concentration of the viral vector is limited by theconcentration that results in an undesirable immune response from apatient.

A variety of adhesives are suitable for the present invention, both foradhering a patch over a heart wound, and for retaining angiogenicmaterial within a wound. Biodegradable polymer and materials aresuitable for mixing with the therapeutic agents as described withrespect to the other embodiments above. One adhesive is a hydrogelcomposed of gelatin and poly(L-glutamic acid)(PLGA). The hydrogel isformed by chemically cross linking gelatin and poly(L-glutamic acid).Another adhesive is fibrin glue. One suitable fibrin glue includesfibrinogen, thrombin, calcium chloride and factor VIII. Another familyof adhesives is cyanoacrylates. Preferred cyanoacrylates includebutyl-2-cyanoacrylate (Histoacryl), ethyl-2-cyanoacrylate, andoctyl-2-cyanoacrylate. Gelatin-resorcinol formaldehyde-glutaraldehyde isanother suitable adhesive.

Applicants believe many polymers having suitable adhesive properties canalso be utilized, including without limitation: polyurethanes havingamino groups, di- and trifunctional diols; polyvinyl acetates;polyamides; polyvinyl alcohols; polystyrenes; polylactides;polylactones; block co-polymers including polyesters, polyamides, andpolyurethanes; and combinations and mixtures thereof.

Growth factors, angiogenic substances and biodegradable carriers andadhesives can be applied internally to punctures within heart chamberwalls, externally to external heart wounds, and incorporated into tubesor spikes for implantation into the myocardium or other organs or solidtumors.

It is anticipated that the patch of the present invention can be used totreat heart failure, heart tissue following myocardial infarction andcancers, in addition to ischemic tissue. In each instance, thetherapeutic agents described above with respect to those conditionscould be incorporated into the patch for delivery to the tissue. In thecase of heart failure, the treatment of heart tissue followingmyocardial infarction and the treatment of cancer, it is believed thatthe patch would be placed directly on, or in close proximity to thetissue to be treated.

FIG. 8 is a schematic view of an alternate catheter assembly 110including a dosage actuator gun 112 and catheter 114. Catheter assembly110 can be used to inject the growth factors, angiogenic materials andother substances in accordance with the present invention. Catheter 24can be used for percutaneous myocardial revascularization (PMR) ofischemic heart tissue delivery of agents to the myocardium of a patientsuffering from congestive heart failure, delivery of agents to salvageinjured myocardium following myocardial infarction, and to inhibitgrowth of cancerous tissues by delivering agents to organs such as thebladder, liver or kidneys.

Gun 112 includes a body 116. Slidably disposed within body 116 andschematically shown in FIG. 7 is a syringe 118, slider body 120 andplunger 124. Syringe 118, slider body 120 and plunger 124 are slidableproximally and distally as shown by the arrows adjacent these respectiveelements. Trigger 122 is pivotally connected about pin 123 to body 116.It can be appreciated that those skilled in the art of mechanical designcould readily fashion a gun 112 based on the schematic descriptionherein.

Catheter 114 includes an inner tubular shaft 126. Inner tubular shaft126 includes a sharpened distal end 127. Like syringe 118, slider 120and plunger 124, inner shaft 126 can be moved proximally or distally asshown by the arrows. More particularly, inner shaft 126 can be movedfrom a proximal position A wherein tip 127 is disposed within an outershaft 129 of catheter 114 to a second position B, wherein tip 127 isdisposed distally of outer shaft 129.

Syringe 118 includes an inner chamber 130 for containing a dosage of adrug or other fluid. Disposed at the distal end of plunger 124 is aplunger seal 132. Syringe 118 including plunger seal 132 preferably areprepacked to contain a quantity of drug, agent or other fluid prior toplacement in gun 112. Syringe 118 includes a Luer fitting 128 or similarattachment device to fluidly connect inner shaft 126 to syringe 118. Theproximal ends of plunger 124 includes a handle 134. Handle 134 can beused to rotate plunger 124 about its longitudinal axis within housing116. Plunger 124 includes a plurality of teeth 136 extending therefrom.Syringe 118 also includes a cradle 138 in which is disposed a one-wayplunger lock 140 which is biased toward plunger 124 by spring 142. Lock140 includes one or more teeth having a slope which allows teeth 136 ofplunger 124 to be advanced distally thereover, but engages with teeth136 to prevent plunger 124 from being withdrawn proximally. Plunger 124can, however, be withdrawn proximally if it is rotated about itslongitudinal axis by using handle 134 such that teeth 136 are disposedaway from lock 140, for example, pointed upward rather than downward asshown in FIG. 8.

Slider 120 includes a syringe restraint member 144 which includes asurface engageable with cradle 138 of syringe 118. A plunger advancingmember 146 is pivotally attached to slider 120 by pin 148. A spring 150biases advancing member 146 toward a vertical position as shown in FIG.8. As slider 120 moves proximally relative to plunger 124, advancingmember 148 pivots downwardly as shown by the arrow allowing slider 120to move proximally relative to plunger 124. Advancing member 146,however, will pivot back to the vertical position after passing over atooth 136 and be braced in the vertical position by slider 120 to engagethe vertical proximal side of one of the teeth 136. Slider 120 includesa slot 152. A pin 156 extends through an end of trigger 122 and isslidable within slot 152. A spring 158 biases trigger 122 into theposition shown. Trigger 122 is, however, pivotable in the directionshown by the arrow about pin 123 between the position shown and anadjustment screw 160. Adjustment screw 160 has a distal end 161 which isengageable with trigger 122 to limit the pivoting of trigger 122 in aclockwise direction about pin 123.

Catheter 114 includes a preferably radiopaque, atraumatic hood 163 atits distal end and a manifold 164 at its proximal end. Manifold 164includes a port 166 for infusion or withdrawal of fluids from catheter114 through a lumen defined between inner shaft 126 and outer shaft 129.Manifold 164 also includes a flange 168 engageable with a portion ofbody 116 to connect body 116 to catheter 114.

FIG. 9 is a cross sectional view of a portion of the catheter assembly110 including a portion of catheter 114 including syringe 118. Luerfitting 128 includes a threaded portion 170 engageable with a threadedportion 172 of a compatible Luer fitting 174 connected to inner shaft126. Syringe 118 defines an inner shaft receiving lumen 175 sealed withpolymer or rubber seal 176 which can be punctured by a sharpened distalend 167 of inner shaft 126 when threads 162 are advanced into threads170. A fluid connection thus results between the lumen through innershaft 126 and chamber 130. Flange 168 can be part of a seal 171 whichcreates a substantially fluid-tight seal between inner shaft 126 andmanifold 164 while allowing inner shaft 126 to move proximally anddistally in the direction as shown by the arrow within manifold 164 ofouter shaft 129. A spring 178 biases inner shaft 126 distally relativeto manifold 164 and outer shaft 129. The travel of inner shaft 126distally is limited by engagement of a stop disc 180 with stop ring 182of manifold 164.

FIG. 10 is a cross sectional view of a preferred embodiment of catheter114 including inner shaft 126 and outer shaft 129. As shown in FIG. 10,outer shaft 129 is connected by suitable heat adhesive to manifold 164.Outer shaft 129 includes a proximal portion 184 which is preferably aco-braided member having, for example, an inner and outer layer of PEBAand a stainless steel reinforcing braid disposed therebetween. Outershaft 129 also preferably includes a distal portion including a springcoil 188 and an outer polyethylene sheath 186. Connected to the distalend of sheath 186 is hood 163. Hood 163 is preferably formed from anatraumatic material and can include radiopaque material to enhancevisibility by fluoroscopy. Inner tube 126 preferably includes a proximalportion 190 which can be formed from, for example, heat treatedstainless steel and a distal portion 192 which is preferably formed froma Nitinol hypotube. A needle 194 having a distal tip 127 is preferablyattached to the distal end of distal tube 192 by a swage collar 196,which may be radiopaque, can engage with hood 163 to limit the distaltravel of inner shaft 126 relative to outer shaft 129.

It can be appreciated by those skilled in the art that there arenumerous materials which can be advantageously used to construct theapparatus disclosed herein. These materials should be selected in viewof the use to which the apparatus is put.

In use, catheter 114 can be advanced into a chamber of the heart, forexample, the left ventricle through a femoral, brachial or carotidartery approach similar to catheter 24 of FIG. 1. Hood 163 of catheter114 is brought into contact with the endocardium of the chamber at aselected location. Chamber 130 of syringe 118 is preferably preloadedwith a drug or growth factor of the type, for example, as describedpreviously. Trigger 122 is then pivoted in a clockwise direction fromthe position shown in FIG. 8 toward set screw 160. This will causeslider 122 to slide in a distal direction. When trigger 122 is in theposition shown in FIG. 8, tip 127 of inner shaft 126 will be in positionA, withdrawn into outer shaft 129. As slider 120 is slid distally,however, restraint member 144 will also advance distally allowingsyringe 118, inner shaft 126 and tip 127 to advance distally under theinfluence of spring 178 such that distal tip 127 will be disposed inposition B distally of hood 163. When tip 127 is in position B, stopplate 180 will engage stop ring 182 as shown in FIG. 8. When tip 127 isin position A, however, plate 180 will be spaced proximally from ring182.

Substantially simultaneously with the advancement of tip 127 fromposition A to position B, plunger advancing member 146 will engage theproximal side of one of the teeth 136 and advance plunger 136 distallyinto reservoir 130 to advance a dosage of drug or growth factor throughinner shaft 126 and out tip 127 which, in position B would be disposedwithin the myocardium. The amount of the dosage can be regulated bylimiting the travel of trigger 122 by adjusting screw 160. It can beappreciated that ring 182 should limit the travel in the distaldirection of inner shaft 126 and syringe 118 to a distance less than thedistal travel of plunger 124 such that there can be relative advancementof plunger 124 into chamber 130 to advance drug or growth factor throughinner shaft 126.

When trigger 122 is released, it will pivot in a counterclockwisedirection back to the position shown in FIG. 8 under the influence ofspring 158. As trigger 122 pivots in a counterclockwise direction backto its original position, plunger 124, and advancing member 146 pivotsin a clockwise direction to slide over the slopped proximal end of oneor more teeth 136. Syringe 118 and inner shaft 126 are slid proximallyby the engagement of member 144 with cradle 138. Once trigger 122 hasattained its original position, the trigger can be pulled again toadvance tip 127 and deliver another dosage of drug or growth factor tothe myocardium.

FIG. 11 is a side view of an alternate distal portion of a catheter 114.In this embodiment, catheter 114 includes a hood 263, which like hood163 is preferably made from atraumatic material and can includeradiopaque material to enhance visibility by fluoroscopy. Hood 263,however, includes a larger diameter opening 265. Disposed just proximalhood 263 is an annular shaped brush 198 which is in contact with andsurrounds needle 194. Disposed loosely on needle 194 is a radiopaquemarker band 200 which can be formed from a suitable metal or bio-stableor biodegradable material loaded with a radiopaque agent. Hood 263, asshown in FIG. 11, is disposed against the endocardium proximatemyocardium 28.

In FIG. 12, needle 194 has been advanced distally beyond the distal endof hood 263 such that radiopaque marker 200 is disposed withinmyocardium 128. In FIG. 13, needle 194 has been withdrawn proximallyinto catheter 114 while marker 200 remains behind in myocardium 28.

Marker 200 can be used for mapping purposes, for example, to define atarget zone or perimeter for subsequent PMR treatment. Marker 200 canalso be used chronically for future PMR treatments, diagnosis andmonitoring. Marker 200 can also be coated or impregnated with a growthfactor, drug or other therapeutic agent.

FIG. 14 is a longitudinal cross sectional view of catheter 114 includingan alternate manifold 264 and alternate distal tube 292. Alternatedistal tube 292 is preferably formed from Nitinol hypotube. Tube 292preferably has a distal tip 227 in the form of a lancet tip whichreduces coring of myocardial tissue during use. Each of the tipsdisclosed in the embodiments described above could also be lancet tips.The tips are preferably 30 to 23 gage, although larger or smallerdiameter tips can be used.

Manifold 264 includes a flange 302 which could be used to engage aportion of gun body 116 in a manner similar to that of flange 168 ofmanifold 164 described above. Within manifold 262 includes a pluralityof steps 304, 305 and 306 disposed therein. Disposed proximate theproximal end of proximal portion 190 of inner shaft 126 is an alternateembodiment of a Luer fitting 274, which can engage Luer fitting 128 ofsyringe 118 of gun 116. Luer fitting 274 includes threads 272. At thedistal end of Luer fitting 274 is a step engaging member 300. A spring278 is fixed at its proximal end within manifold 274 and at its distalend to Luer fitting 274. Spring 278 is biased to draw Luer fitting 274distally.

FIG. 15 is a view of the proximal end of manifold 264 taken from FIG.14. Steps 304, 305 and 306 can be seen within manifold 264. It can beappreciated by reference made to FIG. 14 that each of the steps isdisposed successively more distally than the preceding step.

FIG. 16 is a view of the distal end of Luer fitting 274 taken from FIG.14. Elongate step engaging member 300 can be seen. It can be appreciatedthat if step engaging member 300 has a length approximately equal to,but less than the inside diameter of manifold 264, it can slide withinmanifold 264 to engage against steps 304, 305 or 306 depending upon theangular position of step engaging member 300 about the longitudinal axisof catheter 114. The more distally disposed the step within manifold264, the more distally step engaging member 300 can move within manifold264 prior to engaging a given step.

It can be appreciated that the further engaging member 300 advancesdistally, the farther inner shaft 126 and thus distal tip 227 willadvance distally. Thus, using manifold 264 and Luer fitting 274, thedepth of penetration into the heart wall of tip 227 can be controlled.It is, in fact, contemplated that the depth of penetration could beadjusted such that tip 222 would completely penetrate the heart wall todispose tip 227 between the epicardium and the pericardial. sac. If tip227 is disposed in such a location, catheter 114 could be used todeliver drugs, growth factors or other therapeutic agents or fluidswithin the pericardial sac.

It can be appreciated that the distal movement of inner shaft 126 can belimited by steps 304, 305 or 306 or manifold 264, by configuration asshown with respect to manifold 164 above, or by swage 196 engaging hood163 as shown in FIG. 10. By relying on a stop disposed at the distal endof catheter 114, the depth of penetration of inner shaft tip 127 intothe myocardium can be more consistently controlled. This is facilitatedby making the length of inner shaft 126 sufficiently long thatregardless of the bending of catheter 114 along the atrial access path,swage 196 will engage hood 163 when shaft 126 is advanced distally. Itcan also be appreciated that a variable depth control device such asthat described with connection to manifold 264 could be disposed at thedistal end of catheter 114.

FIG. 17 is a cross sectional view of an alternate embodiment of amanifold 350 in accordance with the present invention. Manifold 350 canbe disposed at the proximal end of outer shaft 129. Inner shaft 126 canextend through outer shaft 129 into manifold 350. Manifold 350preferably includes a housing 352 having on one side a lever arm 354extending therefrom, in a proximal direction. Lever arm 354 ispreferably disposed adjacent an elongate, longitudinally extendinggroove 356 defined in housing 352. Lever arm 354 preferably extends overan area 358 between lever arm 354 and groove 356. Lever arm 354preferably includes a restraining notch 360 disposed distally of itsproximal end 362. A strut 364 extends from lever arm 354 proximatedistal end 362. Housing 356 is preferably formed from a polymer or othermaterials as known to those skilled in the art. The material from whichlever arm 354 is formed is preferably elastic enough that it can be bentor pressed inwardly toward groove 356.

Slidably disposed within housing 352 is a fitting 366 which can be aLuer fitting having threads 368. Fitting 366 is slidable proximally anddistally in the direction shown by the arrows. Fitting 366 is preferablyconnected at its distal end to inner shaft 126 and preferably defines alumen 174 extending therethrough in fluid communication with the lumenthrough inner shaft 126. The catch arm 370 extends in a distal directionto its distal end 372. Fitting 366 is preferably formed from a polymeror other material known to those skilled in the art. The material fromwhich catch arm 370 is formed is preferably elastic enough that arm 370can be pressed inwardly toward groove 356.

A helical spring coil 376 is preferably disposed around a portion ofinner shaft 126. Spring 376 has a proximal end and a distal end. Theproximal end of spring 376 is connected to the distal end of fitting 366and the distal end of spring 376 is connected to an anchor 378 extendingfrom housing 352. As shown in FIG. 17, spring 376 has been elongated bypulling fitting 366 proximally such that distal end 372 of catch arm 370engages notch 360 of lever arm 354 and strut 364 of arm 354 restsagainst a portion of catch 370. In this configuration, fitting 366 is ina first position disposed proximally within housing 352 such that distalend 127 of inner shaft 126 is disposed within outer shaft 129. Fitting366 can be released from the first position and moved proximally bydepressing proximal end 362 of lever arm 354 toward catch 370. Thedistal end of catch arm 372 will then disengage from notch 360 such thatcatch arm 370 moves into space 358 as fitting 366 moves distally to asecond position as spring 376 recoils. In the second position, distalend 127 of inner shaft 126 extends beyond hood 163 of outer shaft 129(as shown in FIG. 10). The amount of travel distally into the secondposition is limited by engagement of swage 196 with hood 163.

Numerous characteristics and advantages of the invention covered by thisdocument have been set forth in the foregoing description. It will beunderstood, however, that this disclosure is, in many respects, onlyillustrative. Changes may be made in details, particularly in matters ofshape, size, and arrangement of parts without exceeding the scope of theinvention. The invention's scope is, of course, defined in the languagein which the appended claims are expressed.

1. A catheter for placement of an in situ implant, comprising: a firstelongate shaft having a proximal end and a distal end, the first shaftdefining a first lumen therethrough; a second elongate shaft having aproximal end and a distal end, the second shaft defining a second lumentherethrough; a first sharpened distal tip disposed at the distal end ofthe first shaft, the first distal tip defining a lumen therethrough influid communication with the first lumen; and a second sharpened distaltip disposed at the distal end of the second shaft, the second distaltip defining a lumen in fluid communication with the second lumen;wherein the first shaft and the second shaft are fixedly secured to oneanother at the distal end of the first shaft and the distal end of thesecond shaft such that the distal end of the first shaft does not moverelative to the distal end of the second shaft.
 2. The catheter of claim1 wherein the first sharpened distal tip extends beyond the secondsharpened distal tip.
 3. The catheter of claim 1 wherein the firstelongate shaft comprises a polymer and the first sharpened distal tipcomprises a metal.
 4. The catheter of claim 3 wherein the secondelongate shaft comprises a polymer and the second sharpened distal tipcomprises a metal.
 5. The catheter of claim 1 wherein the first elongateshaft and the second elongate shaft are welded together at the distalend of the first shaft and the distal end of the second shaft.
 6. Thecatheter of claim 1 wherein the first elongate shaft and the secondelongate shaft are at least 0.5 meters in length.
 7. The catheter ofclaim 1 wherein the first sharpened distal tip is angled in a firstdirection and the second sharpened distal tip is angled in a seconddirection, the second direction being different from the firstdirection.
 8. A catheter for placement of an in situ implant,comprising: a first elongate shaft having a proximal end and a distalend, the first shaft defining a first lumen therethrough; a secondelongate shaft having a proximal end and a distal end, the second shaftdefining a second lumen therethrough; a first sharpened distal tipdisposed at the distal end of the first shaft, the first distal tipdefining a lumen therethrough in fluid communication with the firstlumen; and a second sharpened distal tip disposed at the distal end ofthe second shaft, the second distal tip defining a lumen in fluidcommunication with the second lumen; wherein the first elongate shaftcontains a polymer; and wherein the second elongate shaft contains across-linking agent.
 9. The catheter of claim 8 wherein thecross-linking agent is mixed with a contrast solution.
 10. The catheterof claim 8 wherein the polymer is premixed with therapeutic.
 11. Thecatheter of claim 10 wherein the polymer is alginate polymer.
 12. Thecatheter of claim 8 wherein the position of the distal end of the secondshaft is substantially fixed relative to the position of the distal endof the first shaft.
 13. The catheter of claim 12 wherein the distal endof the first shaft is secured to the distal end of the second shaft by aweb.
 14. The catheter of claim 12 wherein the distal end of the firstshaft is secured to the distal end of the second shaft by an adhesiveweld.
 15. A catheter for placement of an in situ implant, comprising: afirst elongate shaft having a proximal end and a distal end, the firstshaft defining a first lumen therethrough; a second elongate shafthaving a proximal end and a distal end, the second shaft defining asecond lumen therethrough; a first sharpened distal tip disposed at thedistal end of the first shaft, the first distal tip defining a lumentherethrough in fluid communication with the first lumen; and a secondsharpened distal tip disposed at the distal end of the second shaft, thesecond distal tip defining a lumen in fluid communication with thesecond lumen; wherein the first shaft is formed from a biocompatiblepolymer; and wherein the position of the distal end of the second shaftis substantially fixed relative to the position of the distal end of thefirst shaft.
 16. The catheter of claim 15 wherein the first elongateshaft contains a polymer, and wherein the second elongate shaft containsa cross-linking agent.